Proteomics Strategies to Analyze HPV-Transformed Cells: Relevance to Cervical Cancer

Fabio Di Domenico; Federico De Marco; Marzia Perluigi

Disclosures

Expert Rev Proteomics. 2013;10(5):461-472. 

In This Article

Papillomaviruses & Associated Diseases

The relevance of papillomaviruses (PVs) in human pathology has drastically changed across the past three decades. At the early 80s this group of viruses was poorly known, grossly included in the heterogeneous papovaviridae family on the basis of rough similarities in the non-enveloped capsid and in the circular double stranded DNA and deserved no more than a short paragraphs at the end of textbooks as etiological agents of minor dermatological lesions.[1,2] Today PV are recognized as a specific family of viruses, the Papillomaviridae family, they represent a major issue in human oncology and in human sexually transmitted diseases, their name is synonymous of cervical cancer for the layman although their carcinogenic potential is not restricted to the female genital tract.[3] In more details the PV is a newly recognized family of small non-enveloped viruses. The virus particle, usually 50–55 nm in diameter is composed of two proteins, L1 and L2, encapsidating a double stranded circularly closed DNA of roughly 8000 bp length. Based on sequence analyses more than 300 distinct types of PVs have been identified, including nearly 200 human PVs (HPVs), and their number is expected to grow in the coming years due to further identification in animals.[4] Although remarkable differences have been reported in such a large family, all show a much conserved genomic organization. The viral genome is a double stranded circular DNA molecule of approximately 8000 bp carrying 7–9 genes. All known genes are encoded in one DNA strand and transcription is unidirectional. The genome can be divided into three regions: the E region, which is responsible for the pathogenicity of the virus invariably includes the E1 and E2 genes and, in most cases includes the E6 and E7 genes too. The L region, which invariably codes for late structural proteins L1 and L2[5] and a non-coding region which contains the genetic elements for replication and transcription of viral genome. While the genome structure is conserved the genome sequence is significantly divergent. Entirely based on sequence homologies many different types, species and genera of PV have been identified.[6] Two viral isolates belong to different genera when they share <60% nucleotide sequence in their L1 ORF, whereas are considered of different species when sharing between 60 and 70% identities in the L1 ORF and are considered different types when their identities are comprised between 70 and 90%. A remarkable feature of PVs is their strict species-specificity and within a host species, their very strong predilection for specific cutaneous or mucosal district. Within such a classification all HPVs are comprised in the genera: alpha, beta, gamma, mu and nu PV. Alpha PVs infect cutaneous and oropharyngeal/anogenital mucosal districts, beta PV are typically associated with latent/unapparent cutaneous infections in the general immunocompetent population, gamma PV are associated with benign skin lesions and may be occasionally found in oral mucose, mu PV are usually isolated form benign proliferative lesions of the palmar/plantar sites and nu PV are found in other cutaneous lesions.[7] Within epithelial tissues the major target of HPV infections are the basal keratinocytes. Infection takes place through scratches, abrasions or cuts in the suprabasal layers or in specific anatomical sites where basal keratinocytes are physiologically exposed, such as the squamo-columnar junction in the female genital tract. Once the viral infection is established the viral cycle is strictly linked to the terminal differentiation of the host cell. The early genes are expressed in the basal and suprabasal cells, the viral genome is replicated in the intermediate spinous and granular layers, the structural genes are expressed in the squamous layers and the viral progeny is released into the environment together with the desquamated cells. The infection generally takes a chronicle course with benign epithelial proliferations, minor or negligible clinical symptoms, and eventually regresses spontaneously. Occasionally the infection can divert from this classical 'productive' path, the viral infection is stably retained, the proliferation of infected cell persists indefinitely and invasive neoplasia can eventually occur. This process occurs with relevant frequencies in a restricted number of alpha PV which have been accordingly named high-risk HPV types (HR-HPV) while the cognate low risk HPV term is used to indicate the non-oncogenic viral types.

As a matter of fact the HPV-driven carcinogenesis represents dead end path for the viral infection as transformed cells are not permissive for virion production and no further spread of infection occurs and accordingly it is a very rare event. Nonetheless owing to the very high prevalence of HPV infection in the general population, HPV-related cancers are highly frequent conditions representing the second neoplastic diseases among female population worldwide.[8]

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